1. Field of the Invention
This invention relates to a process for the production of 5,6-dihydroxyindolines by ether cleavage of corresponding ether precursors with hydrogen bromide and subsequent direct crystallization from the aqueous reaction mixture.
2. Statement of Related Art
5,6-Dihydroxyindoline, also known in the literature by the names of cyclodopamine and leuconorepinochrome, and 2-carboxy-5,6-dihydroxyindoline (synonyms: cyclodopa and leucodopachrome) are of considerable significance in the field of medicine and pharmacy and also hair dyes.
For example, natural hair dyes, so-called melanins, are formed in the course of their biosynthesis by oxidative polymerization of 5,6-dihydroxyindole. Accordingly, numerous attempts have been made in the past to use 5,6-dihydroxyindole as a reactive dye precursor in the dyeing of hair. Unfortunately, 5,6-dihydroxyindole is extremely unstable in aqueous solution both in its free form and in the form of its salts and, in the presence of atmospheric oxygen, rapidly forms insoluble, colored oxidation and polymerization products which themselves can no longer be fixed to the hair. Accordingly, attempts to use 5,6-dihydroxyindole itself or salts thereof in dye preparations involve considerable difficulties.
By contrast, it has been proposed to use 5,6-dihydroxyindolines as a pigment precursor in the biomimetic dyeing of hair. In this way, natural hair colors can be obtained with melanin dyes via a 5,6-dihydroxyindole formed in situ without having to accept any disadvantages due to the known stability problems of 5,6-dihydroxyindole.
The preparation of 5,6-dihydroxyindoline was described for the first time by S. N. Mishra and G. A. Swan (J. Chem. Soc. C 1967 1424). The authors obtained a solution of 5,6-dihydroxyindoline in hydrochloric acid by ether cleavage of 5,6-dimethoxyindoline in an autoclave at 150.degree. C. The solution then had to be concentrated by evaporation and the resulting crude product purified from ether/ethanol. Unfortunately, this method is attended by several disadvantages: (1) the ether cleavage in an autoclave involves considerable effort with relatively large batches; (2) to recover the crude product, the reaction solution has to be completely concentrated by evaporation, so that considerable energy costs are incurred and the volume/time yield is reduced, and (3) the recrystallization from readily inflammable organic solvents represents a significant risk from the point of view of safety in use.
On the basis of the synthesis of 5,6-dihydroxyindoline by S. N. Mishra and G. A. Swan's method, M. Piatelli et al. developed an alternative synthesis pathway in which dopamine is first oxidized to norepichrome, the norepichrome is reduced to the leuco compound and the leuco compound is converted into triacetyl dihydroxyindoline. 5,6-Dihydroxyindoline is obtained in crude form from the triacetyl dihydroxyindoline after elimination of the acetyl groups. The purification corresponds to that described by S. N. Mischra and G. A. Swan. Apart from the complicated purification step, this method also has major disadvantages which prevent it from being applied on an industrial scale: (1) the oxidation step has to be carried out with a heavily diluted solution (approximately 0.5 g dopamine per liter) and (2) the intermediate triacetyl dihydroxyquinoline has to be purified by column chromatography.
In complete analogy to this method, the synthesis of 2-carboxy-5,6-dihydroxyindoline was described by H. Wyler and J. Choivini (Helv. Chim. Acta 1961 (51) 1476). They oxidized dopamethyl ester in the form of a highly dilute solution to form dopachrome methyl ester and reduced the dopachrome methyl ester in situ to form the leucodopachrome methyl ester which they then isolated as the triacetyl derivative. The triacetyl derivative was then subjected to acidic hydrolysis to form 2-carboxy-5,6-dihydroxyindoline (leucodopachrome). However, the method is attended by the disadvantages described above. Accordingly, the authors only obtained a few milligrams of product which was used for spectroscopic characterization.
According to EP-A-462 857, 5,6-dihydroxyindoline can be prepared by reaction of 5,6-dimethoxyindoline with aqueous HBr. After the reaction, the hydrobromic acid is distilled off, the residue is taken up in ethanol, treated with active carbon and filtered through Celite. Ethyl ether is then added to crystallize 5,6-dihydroxyindoline. This method is too complicated for industrial application.